The present invention resides in the concept of certain ureylenebis-[(substituted or unsubstituted-phenylenecarbonylimino)bis-(substituted-naphthoic acids)] and salts thereof which are novel compounds useful as inhibitors of connective tissue destruction.
Abnormal destruction of connective tissue by collagenase and/or neutral proteases causes tissue damage and/or tissue dysfunction. In these conditions an inhibitor of connective tissue destruction acting directly or indirectly would be useful in preventing, retarding, or reversing tissue damage and/or collagen diseases.
The term connective tissue refers to a matrix of at least three protein molecules, collagen, proteoglycan and elastin. These molecules play an important role in the structural integrity of normal tissues. Collagen, the most abundant protein in the body occupies a central position in the connective tissue matrix ["Biochemistry of Collagen", Ed. G. N. Ramachandran and A. H. Reddi, Academic Press, New York (1976); P. Bornstein, Ann. Rev. Biochem., 43, 567 (1974); J. Fessler and L. Fessler, Ann. Rev. Biochem., 47, 129 (1978)].
Collagen is, for example, the main structural component of the oral tissue (periodontal ligament, alveolar bone, gingiva, and cementum) [Fullmer, et al., J. Dental Research, 48, 646 (1969)]. Collagen amounts to 40% of cartilage protein, 90% of bone protein, and over 90% of dry dermis. Articular cartilage is the resilient tissue that covers the articulating extremities in synovial joints. It consists of collagen fibres that are intimately meshed in a hydrated gel of proteoglycan.
Proteoglycan, as it exists in cartilage, is a molecule in which sulfated polysaccharide chains are covalently linked to a protein backbone ["Dynamics of Connective Tissue Macromolecules", Ed. P. M. Burleigh and A. R. Poole, North Holland, Amsterdam (1975)].
Elastin is a major connective tissue component of pulmonary structure ["Elastin and Elastic Tissue", Ed. L. B. Sandberg, W. R. Gray, and C. Franzblau, Plenum Press, New York (1977)]. The breakdown of elastin of pulmonary connective tissue is considered the primary event in pulmonary emphysema [A. Janoff in "Prosteases and Biological Control", Cold Spring Harbor Conference on Cell Proliferation, 2, 603 (1975)].
Degradation of fibrous collagen is initiated by a combination of neutral proteases and tissue collagenase as an integral part of a complex immunopathological process which results in the loss of collagen from normal tissue. Under normal conditions cellular mechanisms maintain a careful balance between the rates of collagen synthesis and degradation. However, in certain pathological conditions, the ensuing elevated levels of neutral proteases and collagenase can result in rapid collagen degradation and tissue dysfunction. For example, in periodontal disease, the generated elevated levels of neutral proteases and collagenase in the gingival crevicular fluid rapidly degrade the fibrous collagen supporting the teeth. Periodontal pockets result ultimately from collagen degradation, and as these pockets deepen, support of tooth is lost and alveolar bone is resorbed [K. Ohlsson, I. Ohlsson, and G. I. Basthall, Acta Odontol. Scand., 32, 51 (1974); L. M. Golub, S. Kenneth, H. McEwan, J. B. Curran, and N. S. Ramamurthy, J. Dental Research, 55, 177 (1976); L. M. Golub, J. E. Stakin and D. L. Singer, J. Dental Research, 53, 1501 (1974); L. M. Wahl, S. M. Wahl, S. E. Mergenhagen, and G. R. Martin, Proc. Natl. Acad. Sci. U.S., 71, 3598 (1974); Science, 187, 261 (1975)].
In arthritic conditions such as in rheumatoid arthritis, septic arthritis, and osteoarthritis elevated degradation of collagen and proteoglycan initiate rapid destruction of articular tissue [J. M. Evanson, J. J. Jefferey, and S. M. Krane, Science, 158, 499 (1967); E. D. Harris, D. R. Dibona and S. M. Krane, J. Clin. Invest., 48, 2104 (1969); E. D. Harris, Rheumatoid Arthritis, Medcom. Press, N.Y. (1974); Z. Werb, C. L. Mainardi, C. A. Vater and E. D. Harris, New Eng. J. Med., 296, 1017 (1977); J. M. Dayer, R. G. Russell and S. M. Krane, Science, 195, 181 (1977); E. D. Harris, C. A. Vater, C. L. Mainardi and Z. Werb, Agents and Actions, 8, 35 (1978); D. E. Woolley, E. D. Harris, C. L. Mainardi and C. E. Brinkerhoff, Science, 200, 773 (1978); E. D. Harris, C. S. Faulkner, F. E. Brown, Clin. Orthoped., 110, 303 (1975); M. G. Ehrlich, H. J. Mankin, H. Jones, R. Wright and C. Crisper, J. Bone Jt. Surg., 57A, 565 (1975); S. Gordon, W. Newmand and B. Bloom, Agents and Action, 8, 19 (1978); "Mechanisms of Tissue Injury With Reference to Rheumatoid Arthritis", Ed. R. J. Perper, Ann. N.Y. Acad. Sci., 256, 1-450 (1975)].
Increased collagen degradation in bone can result in abnormal bone destruction as in osteoporosis [C. G. Griffith, G. Nichols, J. D. Asher and B. Flannagan, J. Am. Med. Assoc., 193, 91 (1965); B. Gardner, H. Gray and G. Hedyati, Curr. Top. Surg. Res., 2, 175 (1970); B. Gardner, S. Wallach, H. Gray and R. K. Baker, Surg. Forum, 22, 435 (1971)]. Collagenase activity has also resulted in tissue damage in cholesteatoma [M. Abramson, R. W. Schilling, C. C. Huang and R. G. Salome, Ann. Otol. Rhinol. Faryngol., 81, 158 (1975); M. Abramson and C. C. Huang, Laryngoscope, 77, 1 (1976)]. In corneal ulcerations that progress to loss of corneal integrity and function, collagenase has been implicated as a direct factor in corneal destruction [S. I. Brown, C. W. Hook and N. P. Tragakis, Invest. Ophthamol., 11, 149 (1972); M. B. Berman, C. H. Dohlman, P. F. Davison, and M. Ghadinger, Exptl. Eye Res., 11, 225 (1971)]. Elevated levels of collagenase have also been observed in patients with epidermolysis bullosa, and a group of related genetic diseases of the skin [E. A. Bauer, T. G. Dahl, and A. Z. Eisen, J. Invest. Dermatology, 68, 119 (1977)].
Increased breakdown of elastin of the lung tissue by neutral proteases (elastase) may contribute to the lesions in pulmonary emphysema [I. Mandel, T. V. Darmle, J. A. Frierer, S. Keller and G. M. Turino, Elastin and Elastic Tissue, Ed. L. B. Sandberg, W. R. Gray and C. Fransblau, Plenum Press, N.Y., p. 221 (1977)].
A variety of substances, both naturally occurring and synthetically prepared, have been found to be inhibitors of connective tissue destruction, e.g., inhibitors of collagen degradation, that is, as collagenase inhibitors. Such substances include, for example, ethylenediaminetetraacetate, 1,10-phenanthroline, cysteine, dithiothretol and sodium auriothiomalate [D. E. Woolley, R. W. Glanville, D. R. Roberts and J. M. Evanson, Biochem J., 169 265 (1978); S. Seifter and E. Harper, Chap. 18, "The Collagenases" in The Enzymes (3rd Edition), 3, 649-697, Ed. by P. D. Boyer, Academic Press, N.Y. (1971)]. In the eye, a number of studies using collagenase inhibitors directly applied to corneal ulcerations have been reported. Calcium ethylenediaminetetraacetate and acetylcysteine reduce the frequency of ulceration in the alkali burned rabbit [M. Berman and C. Dohlman, Arch. Ophthamol., 35, 95 (1975)]. Both cysteine and acetylcysteine have been effective in the treatment of acute and chronic corneal ulceration in the human, although the latter compound was preferred because of its greater stability [S. I. Brown, N. P. Tragakis and D. B. Pease, Am. J. Ophthalmol., 74, 316 (1972); M. Berman, Trace Components of Plasma: Isolation and Clinical Significance, 7th Annual Red Cross Symposium, p. 225, Alan. R. Liss, Inc., N.Y. (1976)].
Naturally occurring collagenase inhibitors include the serum components .alpha..sub.2 -macroglobulin and .beta.1-anticollagenase [D. E. Woolley, R. W. Glanville, D. R. Roberts and J. M. Evanson, Biochem. J., 169, 265 (1978)].
While some compound may inhibit the destructive effect of collagenase on connective tissue by acting directly on collagenase itself, other compounds may inhibit such destruction by coating, binding or competing with sights on the connective tissue in such a manner as to prevent collagenase from attacking it. The present invention, however, is not to be restricted or limited to any particular mechanism or mode of action. Suffice it to say, that the compounds of this invention have utility as inhibitors of connective tissue destruction albeit in whatever manner or mode.
U.S. Pat. No. 2,687,436 discloses substituted 3-(2-naphthyl)-cyclohexanes useful in the treatment of collagen diseases. British Pat. Nos. 856,357 and 1,246,141 disclose 2-aryl-hexahydro-quinolizines and 1-hydroxylpraline derivatives, respectively, useful for treating diseases affecting connective tissue. The closest known structurally related compound to those of the present invention and disclosed as having collagenase inhibiting activity is found in Thromb. Res., 10(4), 605-11 (1977), wherein the trypanocidal agent trypan blue is reported as inhibiting the activity of collagenase, or a proteinase contaminant in the collagenase preparation. It is interesting, however, that in this same article, the ureide Suramin is reported as not inhibiting the action of collagenase. The closest known ureides to those of the present invention, and not disclosed as inhibitors of connective tissue destruction or as collagenase inhibitors are those ureides found in Journal of the Chemical Society, 3069 (1927), and in U.S. Pat. Nos. 1,218,654 and 1,308,071. The generic disclosure of the '071 patent encompasses a vast number of ureides and with proper selection, among the many possible variables, some of the compounds of this invention may be encompassed within this broad generic disclosure. However, such disclosure by itself does not anticipate or render obvious the invention claimed herein.